Technical Report abstract
Nature Medicine 15, 104 - 109 (2008)
Published online: 7 December 2008 | doi:10.1038/nm.1854
Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes
Yasuteru Urano1,2, Daisuke Asanuma1, Yukihiro Hama3,5, Yoshinori Koyama3,5, Tristan Barrett3,5, Mako Kamiya1, Tetsuo Nagano1, Toshiaki Watanabe4, Akira Hasegawa4, Peter L Choyke3 & Hisataka Kobayashi3
A long-term goal of cancer diagnosis is to develop tumor-imaging techniques that have sufficient specificity and sensitivity. To achieve this goal, minimizing the background signal originating from nontarget tissues is crucial. Here we achieve highly specific in vivo cancer visualization by using a newly designed targeted 'activatable' fluorescent imaging probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH–activatable probes based on the boron-dipyrromethene fluorophore were synthesized and then conjugated to a cancer-targeting monoclonal antibody. As proof of concept, ex vivo and in vivo imaging of human epidermal growth factor receptor type 2–positive lung cancer cells in mice was performed. The probe was highly specific for tumors with minimal background signal. Furthermore, because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. The design concept can be widely adapted to cancer-specific, cell surface–targeting molecules that result in cellular internalization.
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
- PRESTO, Japan Science and Technology Agency, 3-5 Sanbancho, Chiyoda, Tokyo 102-0075, Japan.
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Building 10, Room 1B40, Mail Stop Code 1088, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
- Molecular Diagnostic Technology Group, Advanced Core Technology Department, Research and Development Division, Olympus Corporation, 2-3 Kuboyama-cho, Hachioji, Tokyo 192-8512, Japan.
- Present addresses: Department of Radiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan (Y.H.); Department of Diagnostic and Interventional Radiology, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan (Y.K.); Department of Radiology, Addenbrooke's Hospital, Cambridge University Teaching Hospitals National Health Service Foundation Trust, Hills Road, Cambridge, CB2 2QQ, UK (T.B.).
Correspondence to: Yasuteru Urano1,2 e-mail: urano@mol.f.u-tokyo.ac.jp
Correspondence to: Hisataka Kobayashi3 e-mail: kobayash@mail.nih.gov
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